Skip to main content

Cytomegalovirus infection as an underestimated trigger for checkpoint inhibitor-related pneumonitis in lung cancer: a retrospective study

Clinical and Translational Oncology volume 23, pages 389–396 (2021)Cite this article

Abstract

Objectives

Checkpoint inhibitor-related pneumonitis (CIP) is a rare but potentially fatal complication of immune checkpoint inhibitors (ICIs). At present, the mechanism of CIP is not completely clear. Cytomegalovirus (CMV) infection is widespread in the population. Chemotherapy and radiotherapy can lead to the reactivation of CMV. We aimed to investigate the association between CMV infection and CIP.

Materials and methods

We retrospectively identified all lung cancer patients treated with ICIs at our institute from January 2016 to May 2020. The association between the development of CIP and CMV infection status was analyzed.

Results

Among 251 cases analyzed, 29 (11.6%) patients with CIP were identified, of whom 12 (4.78%) cases had grade 3–4 CIP. All 12 patients with grade 3–4 pneumonitis were CMV-IgG-positive, indicating a previous CMV infection. Except for one CMV-DNA-positive patient, the other patients were CMV-DNA-negative. All but one patient was CMV pp65 antigen-positive, indicating an early reactivation of the virus. The histological features of CMV pneumonia were not found in all available lung tissues, including lung transplantation pathology in one patient and lung biopsies in three patients. Except for one patient who received delayed antiviral therapy, the symptoms improved after glucocorticoid combined with antiviral therapy.

Conclusions

The use of ICIs can restore the immune function and cause an immune response to CMV antigen while the infection is still latent. Our study suggests that CIP may be an immune reconstitution syndrome associated with CMV infection. CMV infection may represent a potentially important trigger for CIP. Patients with severe CIP should be vigilant against CMV infection. The early use of glucocorticoid combined with antiviral therapy is pivotal to good prognosis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig.1

References

  1. Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35(34):3823–9. https://doi.org/10.1200/JCO.2017.72.5069.

    CAS  Article  PubMed  Google Scholar 

  2. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220–9. https://doi.org/10.1056/NEJMoa1809064.

    CAS  Article  PubMed  Google Scholar 

  3. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. New Engl J Med. 2018;378(2):158–68. https://doi.org/10.1056/NEJMra1703481.

    CAS  Article  PubMed  Google Scholar 

  4. Schnitzler MA, Woodward RS, Brennan DC, Spitznagel EL, Dunagan WC, Bailey TC. The effects of cytomegalovirus serology on graft and recipient survival in cadaveric renal transplantation: implications for organ allocation. Am J Kidney Dis. 1997;29(3):428–34.

    CAS  Article  Google Scholar 

  5. Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):709–17. https://doi.org/10.1200/JCO.2016.68.2005.

    CAS  Article  PubMed  Google Scholar 

  6. Nishino M, Giobbie-Hurder A, HatabuH RNH, Hodi FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol. 2016;2(12):1607–16. https://doi.org/10.1001/jamaoncol.2016.2453.

    Article  PubMed  Google Scholar 

  7. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8. https://doi.org/10.1001/jamaoncol.2018.3923.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Khunger M, Rakshit S, Pasupuleti V, Hernandez AV, Mazzone P, Stevenson J, et al. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials. Chest. 2017;152(2):271–81. https://doi.org/10.1016/j.chest.2017.04.177.

    Article  PubMed  Google Scholar 

  9. Cui P, Liu Z, Wang G, Ma J, Qian Y, Zhang F, et al. Risk factors for pneumonitis in patients treated with anti-programmed death-1 therapy: a case-control study. Cancer Med. 2018;7(8):4115–200. https://doi.org/10.1002/cam4.1579.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tamiya A, Tamiya M, Nakahama K, Taniguchi Y, Shiroyama T, Isa SI, et al. Correlation of radiation pneumonitis history before nivolumab with onset of interstitial lung disease and progression-free survival of patients with pre-treated advanced non-small cell lung cancer. Anticancer Res. 2017;37(9):5199–205. https://doi.org/10.21873/anticanres.11943.

    CAS  Article  PubMed  Google Scholar 

  11. O'Hara GA, Welten SP, Klenerman P, Arens R. Memory T cell inflation: understanding cause and effect. Trends Immunol. 2012;33(2):84–90. https://doi.org/10.1016/j.it.2011.11.005.

    CAS  Article  PubMed  Google Scholar 

  12. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45. https://doi.org/10.1038/ni1443.

    CAS  Article  PubMed  Google Scholar 

  13. Sueki H, Mizukawa Y, Aoyama Y. Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients. J Dermatol. 2018;45(1):3–9. https://doi.org/10.1111/1346-8138.14074.

    Article  PubMed  Google Scholar 

  14. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988–2004. Clin Infect Dis. 2010;50(11):1439–47. https://doi.org/10.1086/652438.

    Article  PubMed  Google Scholar 

  15. Cannon MJ, Schmid DS, Hyde TB. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 2010;20(4):202–13. https://doi.org/10.1002/rmv.655.

    Article  PubMed  Google Scholar 

  16. Franklin C, Rooms I, Fiedler M, Reis H, Milsch L, Herz S, et al. Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis. Eur J Cancer. 2017;86:248–56. https://doi.org/10.1016/j.ejca.2017.09.019.

    Article  PubMed  Google Scholar 

  17. Uslu U, Agaimy A, Hundorfean G, Harrer T, Schuler G, Heinzerling L. Autoimmune colitis and subsequent CMV-induced hepatitis after treatment with ipilimumab. J Immunother. 2015;38(5):212–5. https://doi.org/10.1097/CJI.0000000000000081.

    Article  PubMed  Google Scholar 

  18. Lankes K, Hundorfean G, Harrer T, Pommer AJ, Agaimy A, Angelovska I, et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: Possible role of CMV-mediated immunopathogenesis. Oncoimmunology. 2016;5(6):e1128611. https://doi.org/10.1080/2162402X.2015.1128611.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the Special Fund Project of Science and Technology in Guangdong Province (2017B020247038, to X. Lin),State Key Laboratory of Respiratory Disease-The Independent project (SKLRD-QN-201720, to C. Zhou), State Key Laboratory of Respiratory Disease-The open project (SKLRD-OP-2018011, to C. Zhou), Guangdong High Level University Clinical Cultivation Project (2018–2022) (to C. Zhou) and Xinjiang Kashgar Science and Technology Project (KS2017006, to X. Lin).

Author information

Author notes

  1. Xinqing Lin, Tingting Lu and Shiyue Li contributed equally to this work.

Affiliations

  1. Department of Respiratory and Critical Medicine, Jinling Hospital, Nanjing Clinical School of Southern Medical University, 305# East Zhongshan Road, Guangzhou, Nanjing, 210002, China

    X. Lin & Y. Song

  2. State Key Laboratory of Respiratory Disease, National Clinical Research Centre for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital, Guangzhou Medical University, 151# Yanjiang Road, Guangzhou, 510120, China

    X. Lin, S. Li, X. Xie, X. Chen, J. Jiang, Y. Qin, Z. Xie, M. Liu, M. Ouyang, N. Zhong & C. Zhou

  3. Department of Neurology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China

    T. Lu

Authors
  1. X. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X. Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J. Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y. Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Z. Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N. Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C. Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XL, NZ, YS and CZ contributed to the study concept and design. YS and CZ had full access to all the data and took responsibility for the integrity of the data and the accuracy of the data analysis. XL, XC, JJ, YQ and ZX collected the data. XL and TL contributed to the analysis and interpretation of the data. XL and TL draft the manuscript. ML and MO helped interpret the data and draft the manuscript. All authors contributed to the revisions of and approved the final manuscript.

Corresponding authors

Correspondence to Y. Song or C. Zhou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethics approval and consent to participate

This study was approved by the local Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lin, X., Lu, T., Li, S. et al. Cytomegalovirus infection as an underestimated trigger for checkpoint inhibitor-related pneumonitis in lung cancer: a retrospective study. Clin Transl Oncol 23, 389–396 (2021). https://doi.org/10.1007/s12094-020-02432-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-020-02432-5

Keywords

  • Cytomegalovirus
  • Immune checkpoint inhibitor
  • Checkpoint inhibitor-related pneumonitis
  • Immune-related adverse event
  • Corticosteroids
  • Immune reconstitution syndrome